Ischemic stroke in children and young adults with sickle cell disease in the post‐STOP era

Abstract

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) and Optimizing Primary Stroke Prevention in Sickle Cell Anemia (STOP 2) trials established routine transcranial Doppler ultrasound (TCD) screening, with indefinite chronic red cell transfusions (CRCT) for children with abnormal TCD as standard of care. Implementation failures and limitations to the STOP protocol may contribute to continued ischemic stroke occurrence. In the "Post-STOP" study, we sought to assess the impact of the STOP protocol on the incidence of ischemic stroke in a multicenter cohort of former STOP and/or STOP 2 trial participants. A central team abstracted data for 2851 (74%) of the 3835 children who took part in STOP and/or STOP 2. Data included TCD and neuroimaging results, treatment, laboratory data, and detailed clinical information pertaining to the stroke. Two stroke neurologists independently confirmed each stroke using pre-specified imaging and clinical criteria and came to consensus.Among the 2808 patients who were stroke-free at the start of Post-STOP with available follow-up, the incidence of first ischemic stroke was 0.24 per 100 patient-years (95% CI, 0.18, 0.31), with a mean (SD) duration of follow-up of 9.1 (3.4) [median 10.3, range (0-15.4)] years. Most (63%) strokes occurred in patients in whom the STOP protocol had not been properly implemented, either failure to screen appropriately with TCD (38%) or failure to transfuse adequately patients with abnormal TCD (25%). This study shows that substantial opportunities for ischemic stroke prevention remain by more complete implementation of the STOP Protocol.

Reduction in transcranial doppler ultrasound (TCD) velocity after regular blood transfusion therapy is associated with a change in hemoglobin S fraction in sickle cell anemia

“…The participant with a stroke had TAMMV TCD measurement before regular blood transfusion that was Despite the low incidence rate of ischemic strokes with abnormal TCD measurements after blood transfusion therapy, in a large population of children with SCA, ischemic strokes will occur. 7 A limitation in our study is the small sample size of 22 paired TCD measurements before and after regular blood transfusion therapy for at least a year.…”

“…total hemoglobin levels after starting regular blood transfusion therapy for a median of 2.5 years.The optimal decline of TCD velocity after blood transfusion therapy, if any, that confers a low risk of future strokes after starting regular blood transfusion therapy is unknown. Typically, TCD velocity is not obtained after starting regular blood transfusion therapy because, as in the STOP II Trial, TCD velocity obtained after receiving regular blood transfusion therapy was not predictive of future ischemic strokes 7. Potentially, comparing the expected to the observed decline of…”

MRI detection of brain abnormality in sickle cell disease

“…no observable vasculopathy, non-inferiority of hydroxycarbamide was demonstrated in the TWiTCH trial, a primary stroke prevention trial for SCD children who had received at least 12 months of blood transfusion [21]. Recent epidemiological evidence suggests that there has been a parallel fall in the incidence of stroke in SCD and that screening and treatment strategy is cost-effective [22]. There are, however, well-described limitations, including the relatively low specificity of screening, the lack of research on the utility of screening in adult populations, the unclear evidence-base for management of children with both abnormal TCD and MRA, the burdensome nature of transfusion with complications, such as iron overload, and the continuing risk of progressive arteriopathy (Figures 2 and 5F,G) and stroke [23], as well as other neurological complications [1][2][3][4] (see below), in some patients.…”

Pediatric stroke in the emergency department

“…In a study evaluating the incidence of stroke since instituting TCD screening and chronic transfusion therapy, 2.1% of patients still had AIS. A significant number of these patients had abnormal TCD velocities and the majority had a lack of appropriate TCD screening or insufficient chronic transfusion therapy 27 …”